Cancer is one of the leading causes of human death world-wide, accounting for 7.6 million deaths each year [Siegel R, et al. CA Cancer J Clin, 62, 10 (2012)]. Various therapies have been developed to treat cancer patients such as chemotherapy, radiotherapy and targeted therapy, immunotherapy and gene therapy. For decades, natural products have been a well spring of anticancer drugs and drug leads. According to a recent survey by National Cancer Institute, 74% of anticancer drugs worldwide during 1981-2002 can be traced to or were inspired by natural products [Newman D J, et al. J Nat Prod, 66, 1022 (2003)]. These includes natural products (6%), natural product derivatives (27%), synthetic compounds with natural-product-derived pharmacophores (5%), and synthetic compounds designed on the basis of knowledge gained from a natural product (23%). Since some chemical instability and poor water solubility, as well as its high toxicity to normal cells of the compounds isolated from natural products, their clinic application in the treatment of cancers is limited. Through the structure modification of the active natural compounds is an effective way to identify anti-tumor drug candidate. The resulting modified natural product needs to be effective in killing cancer cells with no and much less toxicity to normal cells, and thereby leads to promising anticancer drugs with no or less side effects in treatment of cancer patients.
Most cancers are characterized by impairment of p53 pathway, either by mutation of the p53 gene (TP53) (Soussi T. Oncogene, 2007, 26: 2145.), or by deregulation of expression of p53 and/or other p53-related components of the pathway (Vogelstein B, et al. Nature, 2000, 408: 307). The importance of p53 function as a tumor suppressors by mediating DNA-damaged cells undergoing apoptosis via its transcriptional regulation of Bax and PUMA, while it also causes cell growth arrest at G0 phase via mediating p21 expression when its induction is limited to certain extent. It is well known that at least 50% of human cancers carry TP53 mutations. Interestingly, the majority of the TP53 alterations are missense mutations leading to loss of its biological function with the expression of full-length point mutants (hereinafter identified also as mut-p53 or mutant p53) that accumulate to high levels in cancer cells. Basing on the high frequency of mutation and on the observation that p53 point mutants are highly abundant in invasive and high metastatic tumors, it has been accepted that mutant p53 proteins were associated with resistance to p53-dependent drugs commonly used in anti-cancer therapy (Iwakuma T, et al. Oncogene, 2007, 26: 2177). Given the active role of p53 mutants in drug resistance, the identification of new efficient chemotherapeutic drugs that could kill cancer cells via p53-independent cascade is desirable. However, the drugs with killing cancer cells via p53-independent manner are also highly toxic to normal cells of patients, which results in high side effects, and subsequently limiting the application of high drug doses and chemotherapeutic courses. Taken with consideration that p53-mediated normal cell growth arrest at G0 phase via p53/p21-dependent manner prevents the normal cells undergoing to apoptosis and that most of human cancer cells with p53 mutations will lost this p53 protection and further undergo to apoptosis upon p53-independent cascade, it may be beneficial to design and synthesize a kind of chemotherapeutic compounds that could lead to apoptosis in cancer cells via p53-independent and p53/Bax-PUNA-dependent pathway, whereas it mediates cell growth arrest of normal cells via p53/p21-dependent pathway, which will protect normal cells from killing of drugs. Thus, this kind of new drugs will be selectively killing cancer cells with no or less toxicity to normal cells, by which reduces their side effects on cancer patients.
In view of the above, a need exists for therapeutic agents, and corresponding pharmaceutical compositions and related methods of treatment of cancer that address selectively killing cancer cells with no or less toxicity to normal cells, and it is toward the fulfillment and satisfaction of that need, that the present invention is directed.